Article

Structure and Assembly Mechanism for Heteromeric Kainate Receptors

Laboratory of Cellular and Molecular Neurophysiology, Porter Neuroscience Research Center, NICHD, NIH, DHHS, Bethesda, MD 20892, USA.
Neuron (Impact Factor: 15.98). 07/2011; 71(2):319-31. DOI: 10.1016/j.neuron.2011.05.038
Source: PubMed

ABSTRACT Native glutamate receptor ion channels are tetrameric assemblies containing two or more different subunits. NMDA receptors are obligate heteromers formed by coassembly of two or three divergent gene families. While some AMPA and kainate receptors can form functional homomeric ion channels, the KA1 and KA2 subunits are obligate heteromers which function only in combination with GluR5-7. The mechanisms controlling glutamate receptor assembly involve an initial step in which the amino terminal domains (ATD) assemble as dimers. Here, we establish by sedimentation velocity that the ATDs of GluR6 and KA2 coassemble as a heterodimer of K(d) 11 nM, 32,000-fold lower than the K(d) for homodimer formation by KA2; we solve crystal structures for the GluR6/KA2 ATD heterodimer and heterotetramer assemblies. Using these structures as a guide, we perform a mutant cycle analysis to probe the energetics of assembly and show that high-affinity ATD interactions are required for biosynthesis of functional heteromeric receptors.

1 Follower
 · 
117 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Here we present the synthesis, pharmacological activity, and molecular docking of novel non-competitive antagonists of GluK2 receptor. The compounds concerned are derivatives of indole and carbazole and are the second reported series of non-competitive antagonists of the GluK2 receptor (the first one was also published by our group). The activity of the indole derivatives is in the micromolar range, as in the case of the first series of non-competitive GluK2 receptor antagonists. We have found that designed carbazole derivatives are devoid of activity. Active indole derivatives interact with the transduction domain of the GluK2 receptor, i.e., the domain which links the transmembrane region of the receptor with the agonist-binding domain. The binding pocket is situated within one receptor subunit.
    Medicinal Chemistry Research 02/2014; 24(2):810-817. DOI:10.1007/s00044-014-1171-1 · 1.61 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that open their ion-conducting pores in response to the binding of agonist glutamate. In recent years, significant progress has been achieved in studies of iGluRs by obtaining numerous structures of isolated water soluble ligand binding and amino terminal domains as well as the first full length crystal structure of GluA2 in the closed, antagonist-bound state. This structural data combined with electrophysiological and fluorescence recordings, biochemical experiments, mutagenesis and molecular dynamics simulations have greatly improved our understanding of iGluR assembly, activation and desensitization processes. This article reviews the recent structural and functional advances in iGluR field and summarizes them in a simplified model of full length iGluR gating.
    The Journal of Physiology 10/2013; 593(1). DOI:10.1113/jphysiol.2013.264911 · 4.54 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The plant glutamate-like receptor homologs (GLRs) are homologs of mammalian ionotropic glutamate receptors (iGluRs) which were discovered more than 10 years ago, and are hypothesized to be potential amino acid sensors in plants. Although initial progress on this gene family has been hampered by gene redundancy and technical issues such as gene toxicity; genetic, pharmacological, and electrophysiological approaches are starting to uncover the functions of this protein family. In parallel, there has been tremendous progress in elucidating the structure of animal glutamate receptors (iGluRs), which in turn will help understanding of the molecular mechanisms of plant GLR functions. In this review, we will summarize recent progress on the plant GLRs. Emerging evidence implicates plant GLRs in various biological processes in and beyond N sensing, and implies that there is some overlap in the signaling mechanisms of amino acids between plants and animals. Phylogenetic analysis using iGluRs from metazoans, plants, and bacteria showed that the plant GLRs are no more closely related to metazoan iGluRs as they are to bacterial iGluRs, indicating the separation of plant, other eukaryotic, and bacterial GLRs might have happened as early on as the last universal common ancestor. Structural similarities and differences with animal iGluRs, and the implication thereof, are also discussed.
    Frontiers in Plant Science 10/2012; 3:235. DOI:10.3389/fpls.2012.00235 · 3.64 Impact Factor